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Alport syndrome

alport syndrome, alport syndrome symptoms
Alport syndrome is a genetic disorder1 affecting around 1 in 50,000 children, characterized by glomerulonephritis, end-stage kidney disease, and hearing loss2 Alport syndrome can also affect the eyes, though the changes do not usually affect sight, except when changes to the lens occur in later life Blood in urine is universal Proteinuria is a feature as kidney disease progresses

The disorder was first identified in a British family by University of Edinburgh Medical School graduate Cecil A Alport in 1927,34 Alport Syndrome once also had the label hereditary nephritis, but this is misleading as there are many other causes of hereditary kidney disease and 'nephritis'

Alport syndrome is caused by an inherited defect in type IV collagen—a structural material that is needed for the normal function of different parts of the body Since type IV collagen is found in the ears, eyes, and kidneys, this explains why Alport syndrome affects different seemingly unrelated parts of the body ears, eyes, kidneys, etc

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Contents

  • 1 Signs and symptoms
    • 11 Hematuria and proteinuria
    • 12 Hearing loss
    • 13 Leiomyomatosis
    • 14 Eye changes
    • 15 Other abnormalities
  • 2 Pathophysiology
    • 21 Genetics
      • 211 Inheritance patterns
  • 3 Diagnosis
    • 31 Biopsy of kidneys or skin
    • 32 Family history
    • 33 Genetic testing
    • 34 Other tests
  • 4 Treatment
    • 41 Kidney disease and renal failure
    • 42 Hearing loss
  • 5 Prognosis
  • 6 See also
  • 7 References
  • 8 External links

Signs and symptomsedit

These descriptions refer to 'classic' Alport Syndrome, which usually causes significant disease from young adult or late childhood life5 Some individuals, usually with milder mutations or 'carrier' status, develop disease later, or show only some of the features of classic disease

Hematuria and proteinuriaedit

Blood in urine is a usual feature of Alport Syndrome from early infancy, identifiable on urine dipsticks In young children, episodes of visible macroscopic haematuria may occur Protein begins to appear in urine as the disease progresses This is now regarded as an indication for treatment with ACE inhibitors

Hearing lossedit

Alport syndrome can also cause hearing loss although some patients are not affected6 Hearing in Alport syndrome patients is normal at birth Hearing loss in affected patients develops progressively, usually at the stage when kidney function is normal, but there is substantial proteinuria However, in some patients, hearing loss is only noted after kidney function has been lost Characteristically the early changes are reduced abililty to hear high frequency sounds, 'high-tone hearing loss' This becomes more severe and affects lower frequencies too Hearing loss is not usually complete in Alport Syndrome, good communication is almost always possible with the use of hearing aidscitation needed

Leiomyomatosisedit

Diffuse leiomyomatosis of the esophagus and tracheobronchial tree has been reported in some families with Alport syndrome Symptoms usually appear in late childhood and include dysphagia, postprandial vomiting, substernal or epigastric pain, recurrent bronchitis, dyspnea, cough, and stridor Leiomyomatosis is confirmed by computed tomography CT scanning or magnetic resonance imaging MRI7

Eye changesedit

Various eye abnormalities are often seen including lenticonus, keratoconus, cataracts as well as retinal flecks in the macula and mid-periphery8 These rarely threaten vision Lenticonus cone-shaped lens can be treated by replacement of the lens, as for cataracts Mild keratoconus can be treated with hard or piggy-back contact lenses, severe cases may require a corneal transplant

Other abnormalitiesedit

Aortic dissection has been described very rarely in patients with early-onset disease5 Leiomyomas, tumours of smooth muscle affecting the oesophagus and female genital tract, may occur in a rare overlap syndrome involving the adjacent COL4A5 and COL4A6 genes9

Pathophysiologyedit

Geneticsedit

Alport syndrome is caused by mutations in COL4A3, COL4A4, and COL4A5, three of six human genes involved in basement membrane type IV collagen biosynthesis Mutations in any of these genes prevent the proper production or assembly of the specialised type IV collagen '345' network found in the glomerulus, which is an important structural component of basement membranes in the kidney, inner ear, and eye It is also found in other locations, including the alveoli of the lungs Basement membranes are thin, sheet-like structures that separate and support cells in many tissues Type IV collagen '112' type is found in both vertebrates and invertebrates, and is the major isoform in most human basement membranes When mutations prevent the formation of 345 type IV collagen network in the glomerulus, the 112 network, which is formed in fetal development but usually replaced by 345, persists into adult lifecitation needed

Inheritance patternsedit

Alport syndrome can have different inheritance patterns depending on which specific mutation is present

  • In most people with Alport syndrome about 85%, the condition is inherited in an X-linked pattern,10 due to mutations in the COL4A5 gene A condition is considered X-linked if the gene involved in the disorder is located on the X chromosome In males, who have only one X chromosome, one altered copy of the COL4A5 gene is sufficient to cause severe Alport syndrome, explaining why most affected males eventually develop kidney failure In females, who have two X chromosomes, a mutation in one copy of the COL4A5 gene usually results in blood in the urine, but most affected females do not develop kidney failure
  • Alport syndrome can also be inherited in an autosomal recessive pattern if both copies of the COL4A3 or COL4A4 gene, located on chromosome 2, have been mutated Most often, the parents of a child with an autosomal recessive disorder are not affected but are carriers of one copy of the altered genecitation needed
  • Past descriptions of an autosomal dominant form are now usually categorized as other conditions11 Notably, conditions associated with giant platelets and associated with mutations of MYH9 are no longer considered to be Alport variants However apparent autosomal dominant transmission of disease associated with mutations in COL4A3 and COL4A4 does occur1213

Clinical utility gene card for: Alport syndrome14

Diagnosisedit

The diagnosis can usually be made on a combination of clinical, family history and biopsy criteria

Biopsy of kidneys or skinedit

To be helpful, kidney biopsies need to be taken before the disease is too advanced Changes on conventional light microscopy are not characteristic, and the possibility of other diagnoses, particularly focal segmental glomerulosclerosis FSGS may be raised Electron microscopy shows a characteristic sequence of changes from thinning of the glomerular basement membrane GBM, developing into areas of thinning and thickening, and finally into a complex appearance with apparent splitting, often described as a 'basketweave' appearance Early or very localised changes on this spectrum are not diagnostic, but the later changes are considered diagnosticcitation needed

Immunohistochemistry or immunofluorescence studies to identify the COL3-4-5 proteins in GBM can be helpful However these studies may be normal in some patients with Alport syndrome, especially milder variants

Skin contains type IV collagen in a '556' network Skin biopsies have been used to show absence of the COL4A5 gene product, but these techniques are not straightforward, only apply to patients with severe COL4A5 mutations, and are not widely available Genetic testing is now a better alternative if kidney biopsy is not possiblecitation needed

Family historyedit

A family history of end stage renal disease with hearing impairment is suggestive of Alport syndrome, but other conditions can cause this combination of abnormalities Most can be distinguished by clinical features The finding of haematuria in relatives is suggestivecitation needed While X-linked inheritance is the most common pattern, genetic testing is revealing that atypical presentations may be more common than currently thought

Genetic testingedit

Genetic testing plays an increasingly important role in confirming the diagnosis where the clinical features do not amount to proofcitation needed

Other testsedit

The use of eye examinations for screening has been proposed15

Treatmentedit

Kidney disease and renal failureedit

In addition to measures for chronic kidney disease CKD of any cause, there is evidence that ACE inhibitors can slow the deterioration of kidney function in Alport Syndrome, delaying the need for dialysis or transplantation16 The development of proteinuria has been recommended as an indication for commencing treatment5

Once kidney failure has developed, patients usually do well on dialysis or with a kidney transplant Very rarely the Alport molecule in the donor kidney causes an aggressive immune response in the recipient, 'Alport post-transplant anti-GBM disease'1718

Gene therapy has been frequently discussed, but delivering it to the podocytes in the glomerulus that normally produce the type IV collagen in the glomerular basement membrane is challenging19

Hearing lossedit

It is not known whether ACE inhibitors or other treatments affect hearing loss For those with classic Alport Syndrome, hearing aids are often required in teenage or young adult yearscitation needed

Prognosisedit

Studies of the life expectancy of patients with Alport syndrome are rare, but one 2012 study of 456 male patients from across Europe who received a kidney transplant found that they had somewhat increased life expectancy compared to matched controls the controls were "randomly selected from the same age, year, and modality categories"20

See alsoedit

  • Samoyed hereditary glomerulopathy, a disease shown to be a model for Alport syndrome21
  • Fechtner syndrome

Referencesedit

  1. ^ Diseases of the Kidney: Alport Syndrome
  2. ^ "Alport syndrome" at Dorland's Medical Dictionary
  3. ^ Lagona E, Tsartsali L, Kostaridou S, Skiathitou A, Georgaki E, Sotsiou F 2008 "Skin biopsy for the diagnosis of Alport syndrome" Hippokratia 12 2: 116–8 PMC 2464308  PMID 18923659 
  4. ^ Alport AC 1927 "Hereditary familial congenital haemorrhagic nephritis" British Medical Journal 1 3454: 504–6 JSTOR 25322864 PMC 2454341  PMID 20773074 doi:101136/bmj13454504 
  5. ^ a b c UK Alport Group "Alport SyndromeL Clinician information" RareRenal Renal Rare Diseases Registry Retrieved 17 February 2016 
  6. ^ Zhou, Jing; Hertz, Jens Michael; Tryggvason, Karl 1992 "Mutation in the α5IV collagen chain in juvenile-onset Alport Syndrome without hearing loss or ocular lesions: Detection by denaturing gradient gel electrophoresis of a PCR product" American Journal of Human Genetics 50 6: 1291–300 PMC 1682577  PMID 1598909 
  7. ^ Alport Syndrome~clinical at eMedicine
  8. ^ Chugh KS, Sakhuja V, Agarwal A, Jha V, Joshi K, Datta BN, Gupta A, Gupta KL 1993 "Hereditary nephritis Alport's syndrome--clinical profile and inheritance in 28 kindreds" Nephrology, Dialysis, Transplantation 8 8: 690–5 PMID 8414153 
  9. ^ Kashtan, CE "Gene Reviews: Alport Syndrome" NCBI Gene Reviews NCBI Retrieved 17 February 2016 
  10. ^ Jais JP, Knebelmann B, Giatras I, De Marchi M, Rizzoni G, Renieri A, Weber M, Gross O, Netzer KO, Flinter F, Pirson Y, Dahan K, Wieslander J, Persson U, Tryggvason K, Martin P, Hertz JM, Schröder C, Sanak M, Carvalho MF, Saus J, Antignac C, Smeets H, Gubler MC 2003 "X-linked Alport syndrome: natural history and genotype-phenotype correlations in girls and women belonging to 195 families: a 'European Community Alport Syndrome Concerted Action' study" Journal of the American Society of Nephrology 14 10: 2603–10 PMID 14514738 doi:101097/01ASN00000900347120574 
  11. ^ "OMIM - ALPORT SYNDROME, AUTOSOMAL DOMINANT" Retrieved 2008-11-24 
  12. ^ Kharrat M, Makni S, Makni K, Kammoun K, Charfeddine K, Azaeiz H, Jarraya F, Ben Hmida M, Gubler MC, Ayadi H, Hachicha J 2006 "Autosomal dominant Alport's syndrome: study of a large Tunisian family" Saudi Journal of Kidney Diseases and Transplantation 17 3: 320–5 PMID 16970251 
  13. ^ Pescucci C, Mari F, Longo I, Vogiatzi P, Caselli R, Scala E, Abaterusso C, Gusmano R, Seri M, Miglietti N, Bresin E, Renieri A 2004 "Autosomal-dominant Alport syndrome: natural history of a disease due to COL4A3 or COL4A4 gene" Kidney International 65 5: 1598–603 PMID 15086897 doi:101111/j1523-1755200400560x 
  14. ^ Hertz JM, Thomassen M, Storey H, Flinter F 2012 "Clinical utility gene card for: Alport syndrome" European Journal of Human Genetics 20 6 PMC 3355248  PMID 22166944 doi:101038/ejhg2011237 
  15. ^ Zhang KW, Colville D, Tan R, Jones C, Alexander SI, Fletcher J, Savige J 2008 "The use of ocular abnormalities to diagnose X-linked Alport syndrome in children" Pediatric Nephrology 23 8: 1245–50 PMID 18343956 doi:101007/s00467-008-0759-4 
  16. ^ Alport Syndrome~treatment at eMedicine
  17. ^ http://wwwedrenorg/pages/edreninfo/alport-syndromephp
  18. ^ Name, Your "EdRen - Edinburgh Royal Infirmary Renal Unit - Alport anti-GBM disease" wwwedrenorg Retrieved 2016-02-17 
  19. ^ Tryggvason K, Heikkilä P, Pettersson E, Tibell A, Thorner P 1997 "Can Alport syndrome be treated by gene therapy" Kidney International 51 5: 1493–9 PMID 9150464 doi:101038/ki1997205 
  20. ^ Temme, Johanna; Kramer, Anneke; Jager, Kitty J; Lange, Katharina; Peters, Frederick; Müller, Gerhard-Anton; Kramar, Reinhard; Heaf, James G; Finne, Patrik 2012-12-01 "Outcomes of Male Patients with Alport Syndrome Undergoing Renal Replacement Therapy" Clinical Journal of the American Society of Nephrology 7 12: 1969–1976 ISSN 1555-9041 PMC 3513741  PMID 22997344 doi:102215/CJN02190312 
  21. ^ Chen D, Jefferson B, Harvey SJ, Zheng K, Gartley CJ, Jacobs RM, Thorner PS 2003 "Cyclosporine a slows the progressive renal disease of alport syndrome X-linked hereditary nephritis: results from a canine model" Journal of the American Society of Nephrology 14 3: 690–8 PMID 12595505 doi:101097/01ASN00000469641583116 

 This article incorporates public domain material from the United States National Library of Medicine document "Alport syndrome" Genetics Home Reference


External linksedit

  • Laboratory for Molecular Diagnostics, Center for Nephrology and Metabolic Disorders, Dr Mato Nagel
  • Alport Syndrome Foundation
  • Alport Foundation of Australia
  • Alport Syndrome Support for Canadians
  • GeneReview/NIH/UW entry on Alport syndrome
  • Alport Syndrome Treatments and Outcomes Registry
  • UK Alport syndrome testing, Molecular Genetics, Guy's Hospital
  • Alport Syndrome at the Mutation Databases at the University of Utah

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